Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH:18]([C:20]4[O:24][N:23]=[C:22]([CH3:25])[N:21]=4)[CH2:19][CH:12]2[CH2:13][C:14](=[O:26])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:27](OCC)=[O:28].[O-]CC.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH:18]([C:20]4[O:24][N:23]=[C:22]([CH3:25])[N:21]=4)[CH2:17][CH:16]2[C:15](=[CH:27][OH:28])[C:14](=[O:26])[CH2:13]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1noc(C2CC3CC(=O)CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C2CC3CC(=O)C(=CO)C(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
9-[(4-Chlorophenyl)sulfonyl]-7-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-one (52) (0.357 g, 0.902 mmol) was dissolved in THF/EtOH (2 mL, 1/1, v/v). Ethyl formate (0.725 mL, 9.02 mmol) was added followed by sodium ethoxide (1.01 mL of 21% solution in EtOH). The resulting mixture was stirred at 50° C. for 1 hour after which the solution was cooled back to room temperature and quenched by the addition of saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to give 9-[(4-chlorophenyl)sulfonyl]-2-(hydroxymethylidene)-7-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-one (53). MS (ESI) 424.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9](Cl)=O.O[CH:15]([C:28]1[CH:32]=[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])OC=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.[Cl:37]CCl>>[Cl:37][CH:28]([C:32]1[CH:9]=[CH:8][O:12][C:31]=1[Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: ClCCl
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(Cl)c1ccoc1[Si](C)(C)C
Reaction time: 0.67 h

Procedure:
Triethylamine (0.55 ml, 3.95 mmol), followed by oxalyl chloride (0.34 ml, 3.95 mmol) was added dropwise to a solution of 3-(1-hydroxytridecyl)-5-trimethylsilylfuran (890 mg, 2.63 mmol) in anhydrous dichloromethane (10 ml) at 0°. After 40 minutes, the reaction was quenched with ice water. Extraction (dichloromethane) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.37 on evaporation gave 3-(1-chlorotridecyl)-2-trimethylsilylfuran as a pale yellow oil, solidified to a colorless solid on storage at -20°.
Reaction SMILES: C([O:4][CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)[C:6]([C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH:12]1[CH2:14][CH2:13]1)([F:10])[C:7]([O-:9])=[O:8])(=O)C.[OH-].[Na+].CO>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:11]([CH:12]2[CH2:14][CH2:13]2)[C:6]([F:10])([CH:5]([OH:4])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[C:7]([OH:9])=[O:8])=[CH:16][CH:17]=1
Reactant: CC(=O)OC(Cc1ccc(F)c(Oc2ccccc2)c1)C(F)(C(=O)[O-])[C@H](c1ccc(Cl)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(F)(C(O)Cc1ccc(F)c(Oc2ccccc2)c1)[C@H](c1ccc(Cl)cc1)C1CC1

Procedure:
A mixture of methyl (2R,3S or 2S,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (Diastereomer B) (0.80 g, 1.50 mmol), aqueous sodium hydroxide (25 ml), methanol (20 ml) and tetrahydrofuran (5 ml) is refluxed for 1 hour. The organic solvents are removed in vacuo, the mixture is diluted with ethyl acetate and acidified to pH 3 with concentrated hydrochloric acid. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless semi solid, which is characterized by 1HNMR and 19FNMR and used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:7]=2[NH:6][C:5]1=[O:38].[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:7]4[N:6]([CH3:39])[C:5](=[O:38])[CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]=4[N:10]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (40 mg, 0.078 mmol) in DMF(1 ml) was added potassium carbonate (32 mg) and methyl iodide (13.2 mg, 0.093 mml) were added. The reaction mixture was stirred at room temperature for 4 h.
Reaction SMILES: [CH2:1]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[Si](Cl)(C)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[C:35]([NH:27][C:26]1[NH:25][C:23](=[O:24])[C:22]2[N:21]=[CH:20][N:19]([C:29]=2[N:28]=1)[C@@H:12]1[O:13][C@H:14]([CH2:17][OH:18])[C@@H:15]([OH:16])[C@H:11]1[O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21

Procedure:
2'-O-nonylguanosine (14.7 g) in pyridine (360 ml) was treated with trimethylsilyl chloride (23.4 ml) and isobutyryl chloride (30.6 ml) as per the procedure of Example 4 to yield crude product (37 g). The crude material was purified by silica gel chromatography (eluted with 90/10 CHCl3 /MeOH) to yield 14.6 g of product re-crystallized from EtOAc. m.p. 168-169° C. 1H NMR (DMSO-d6) δ 0.85 [t, 3, CH3 (nonyl)], 1.14 [m, 18, O--CH2CH2 (CH2)6, CH(CH3)2 ], 1.40 [m, 2, O--CH2CH2 (CH2)6 ], 2.79 [m, 1, CH(CH3)2 ], 3.31-3.63 (m, 4, H-5', O--CH2 (CH2)7 !; 3.96 (m, 1, H-4'), 4.27-4.37 (m, 2, H-2', H-3'); 5.10 (t, 1, 5'-OH, J=5 Hz), 5.18 (d, 1, 3'-OH, J=4 Hz), 5.91 (d, 1, H-1', J=6.6 Hz), 8.31 (s, 1, 8-H), 11.73 (s, 1, C2 amide) and 12.11 (s, 1, N1 amide). Anal. Calcd. for C23H37N5O6 : C, 57.60; H, 7.78; N, 14.60. Found: C, 57.63; H, 7.92; N, 14.62.
Reaction SMILES: [O:1]=[C:2]1[C:6]2C=CC=CC=2C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:36])([CH3:35])[C@@H:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:17])=[O:16].C(O)C.NN.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:2]([NH:3][CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:35])([CH3:36])[C@@H:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:17])=[O:16])(=[O:1])[CH3:6]
Reactant: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 69 %

Procedure:
Adapting procedures or variations thereof according to Duncan et al., J. Org. Chem. 2001, 66, 5237-5240; Shue et al., Bioorg. Med. Chem. Lett. 1996, 6, 1709-1714; and Khan, J. Org. Chem. 1995, 60, 4536-4541, a 100 mL round-bottomed flask was charged with ethyl (2R)-4-{[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (22a) (1.4 g, 2.7 mmol) and 20 mL of a mixture of ethanol (EtOH)/ethyl acetate (EtOAc) (1:1 v/v). Hydrazine (N2H4) (ca. 0.17 mL, 0.17 g, 5.4 mmol) was added at room temperature. The reaction was monitored by LC/MS. Upon completion of the reaction, acetic anhydride (Ac2O) (1.02 mL, 1.1 g, 10.8 mmol) was added to the mixture. The solution was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate (NaHCO3). The organic layer was washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and methanol (MeOH) (EtOAc/MeOH=19:1) as eluent to provide 0.8 g (69% yield) of the title compound (22b) as a colorless oil. Rf=0.50 (EtOAc/MeOH=19:1). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.07 (s, 3H), 1.32 (t, J=6.8 Hz, 3H), 2.00-2.06 (m, 2H), 2.05 (s, 3H), 3.08-3.12 (m, 2H), 3.35 (q, J=6.4 Hz, 2H), 3.83 (s, 1H), 3.97 (d, J=9.2 Hz, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.21-4.27 (m, 2H), 4.36 (d, J=11.2 Hz, 1H), 4.62 (d, J=11.2 Hz, 1H), 5.82-5.86 (br. m, 1H), 7.26-7.35 (m, 5H), ppm. MS (ESI) m/z 430.02 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([C:14]#[N:15])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:23](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[NH2:24]>>[C:14]([C:7]1[C:8]([CH3:13])([CH3:12])[O:9][C:10]2[C:5]([C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[CH:4][CH:3]=[C:2]([NH:24][C:23](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:11]=2)#[N:15]
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C#N
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C#N)=C2c1ccc(F)cc1

Procedure:
The compound obtained in (2) described above (340 mg) and tert-butyl carbamate (380 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (427 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Product: Cc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
19.77 g of 6-methyl-5-(4-methylphenyl)-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 100 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added chloroform and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 19.90 g of 3-chloro-6-methyl-5-(4-methylphenyl)-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxii) of the present invention).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: COCCCOc1cc(F)cc2ccc(C)nc12
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: COCCCOc1cc(F)cc2ccc(C=O)nc12
Yield: 87.3 %

Procedure:
To a solution of 6-fluoro-8-(3-methoxypropoxy)-2-methylquinoline (0.22 g, 0.87 mmol) in dioxane (20 mL) and water (0.2 mL) was added selenium dioxide (0.12 g, 1.0 mmol) and the resultant mixture was heated at reflux for 5 hours. The cooled reaction mixture was filtered through a plug of Celite®, washing the solids with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.20 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[O:25][C:26]=1[CH3:27]>>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[CH3:2]
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Product: CCOC(=O)/C(=C/c1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), (Z)-2-ethoxy-3-(1H-indol-5-yl)-acrylic acid ethyl ester [preparation 1a)] was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole to give (Z)-2-ethoxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-acrylic acid ethyl ester, which was subsequently saponified to yield (Z)-2-ethoxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-acrylic acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4]C=1C.[Li+].[OH-:21]>CO.O>[C:5]([O:21][C:8]([NH:7][C:2]1[N:1]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:17][CH:18]=1)=[O:16])([CH3:17])([CH3:6])[CH3:4]
Reactant: CCOC(=O)CNC(=O)NCc1ccc(N)c(C)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NCC(=O)O)cn1
Temperature: 50 °C
Yield: 195.1 %

Procedure:
51 (7.5 g, 21.3 mmol) was dissolved in 50 ml of MeOH and 50 ml of water, LiOH (4 equivalent, 2.0 g) was added and the reaction mixture was heated to 50° C. for 2 h. The reaction mixture is concentrated and 200 ml of water are added, then extracted twice with AcOEt. The water is acidified to pH 5 with concentrated HCl 36%, then extracted twice with AcOEt. The combine organic phase are dried over Na2SO4, filtered and concentrated to afford 57 (6.74 g, 98%) as a white solid.
Reaction SMILES: [CH:1]1([NH:8][C:9]([C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.Cl.[OH-].[Na+]>CO>[CH:1]1([NH:8][CH2:9][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCCC1)c1cccc2c1Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1c(CNC3CCCCCC3)cccc1-2
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To N-cycloheptyl-1-fluorenecarboxamide (1.00 g, 3.28 mmol) was added a 1M solution of borane-tetrahydrofuran complex in THF (13 ml, 13 mmol) and the mixture was heated at 60° C. for 7.5 hrs. To this reaction mixture were added methanol (0.4 ml) and concentrated hydrochloric acid (3 ml) and the mixture was heated at 60° C. for 0.5 hr. Then, 1N aqueous sodium hydroxide solution (50 ml) was added at room temperature and the mixture was extracted with chloroform (80 ml×2 times). The organic layer was taken, dried and concentrated. To the residue were added ether (30 ml) and 4N hydrogen chloride in ethyl acetate (2 ml) and the resulting white solid was collected by filtration. This solid was dissolved in chloroform (80 ml) and washed with 1N aqueous sodium hydroxide solution (80 ml×1). The Organic layer was dried and concentrated to give 0.90 g of a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+].C[O:26][C:27](=O)[CH:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[OH:1][CH:2]([CH2:21][OH:22])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:27](=[O:26])[CH:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-hexadecylamine (1.0 g, 3.2 mmoles) and potassium hydroxide (0.01 g, 0.18 mmoles) were heated to 85° C. under vacuum and methyl-2-hydroxyoctanoate (0.55 g, 3.2 mmoles) was added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off white solid was obtained (crude yield=1,39 g), and the waxy solid further purified by recrystallization in hot hexane. (Yield=0.88g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:12])=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: Cc1cc(Br)c(C)c(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(Br)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2,3,6-trimethyl phenol (66.2 g; 0.294 mol) in acetone (2 L) was added potassium carbonate (203 g; 1.47 mol) at ambient temperature. Then MeI (91.4 ml; 1.47 mol) was added dropwise over 30 mins. Reaction was stirred overnight at ambient temperature. After this time the mixture was filtered, washing with acetone (2×200 ml) and the filtrate evaporated to give a red solid. The solid was taken up in DCM (1.2 L) and washed with 1M sodium thiosulfate (2×400 ml), half sat. brine (800 ml), dried (anh. MgSO4), filtered and the solvent evaporated to give a red oil (53.8 g; 80%). 1H NMR (300 MHz, CDCl3), δ/ppm; 2.23 (3H, s, Ar—CH3), 2.25 (3H, s, Ar—CH3), 2.32 (3H, s, Ar—CH3), 3.66 (3H, s, Ar—OCH3), 7.23 (1H, s, Ar—H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[NH2:6][C:7]([CH2:11][CH3:12])=[CH:8][C:9]#[N:10].C(C[C:18]([O:20][CH3:21])=[O:19])(=O)CC.C(=O)([O-])[O-].[Na+].[Na+].[C:28]1(C)[CH:33]=[CH:32]C=C[CH:29]=1>CCOCC>[NH2:10][C:9]1[CH:29]=[C:28]([CH2:33][CH3:32])[N:6]=[C:7]([CH2:11][CH3:12])[C:8]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCC(=O)CC(=O)OC
Reactant: Cc1ccccc1
Reactant: CCC(N)=CC#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCc1cc(N)c(C(=O)OC)c(CC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tin tetrachloride (24 ml) in toluene (70 ml) was added to a stirred solution of 3-amino-2-pentenenitrile (10 g) (obtained as described in J. Het. Chem., 1989, 26, 1575) and methyl propionylacetate (13.4 g) in toluene (150 ml). The mixture was heated at reflux for 6 hours and then stirred at ambient temperature for 16 hours. Saturated sodium carbonate solution was added to the stirred mixture until the aqueous phase was basic (pH>9). Ether (200 ml) was added to the mixture and the precipitated tin salts removed by filtration through diatomaceous earth. The organic phase of the filtrate was separated, washed with sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation and the residue was extracted with hot hexane (3×50 ml). The combined hexane extracts were evaporated and the residue was dissolved in minimum of hot hexane. The solution was then cooled at 4° C. for 16 hours when a yellow solid crystallised. The solid (7.3 g) was collected by filtration and purified by flash chromatography eluting with dichloromethane/methanol (1:19 v/v) to give methyl 4-amino-2,6-diethylpyridine-3-carboxylate (B) (6 g) as a light yellow solid, m.p. 75° C.; NMR (CDCl3): 1.25(t,6H), 2.65(q,2H), 2.95(q,2H), 3.9(s,3H), 5.65(broad s,2H), 6.25(s,1H); mass spectrum (chemical ionisation (CI), ammonia): 209(M+H)+.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][C@H:5]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N+:2]=[N-:3].[CH:40](OC(=O)C)=[CH2:41]>>[C:36]([O:35][C:33]([NH:32][C@H:5]1[C@@H:4]([N:1]2[CH:41]=[CH:40][N:3]=[N:2]2)[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6]1)=[O:34])([CH3:38])([CH3:37])[CH3:39]
Reactant: C=COC(C)=O
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Yield: 21.1 %

Procedure:
A solution of di-tert-butyl (4-{(3R,4S,5S)-4-azido-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (0.37 g, 0.67 mmol) in acetic acid ethenyl ester (5.50 mL, 59.7 mmol) in a sealed flask was heated at 115° C. for 40 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica using a CombiFlash® apparatus (50 to 100% EtOAc in hexanes) to give the sub-title compound (81 mg, 21%). LCMS calc. for C28H44N7O6 (M+H)+: m/z=574.3. Found: 574.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1>CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=2)[C:15]([Cl:19])=[CH:14][N:13]=1.[NH2:13][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1cccc(N)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCOC(C)=O
Product: N#CCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: N#CCc1ccccc1N

Procedure:
Example 1229b [3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile was prepared from (3-Amino-phenyl)-acetonitrile and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1223b. Title product was isolated as a beige solid (144 mg, 40%) after silica gel chromatography (ISCO 40 g 0-100% EtOAc in hexanes). 91% HPLC purity, MP=155-157, LCMS 279.11 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.45 (dd, J=7.8 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 3.82, s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([C:23]3[C:28]([Cl:29])=[CH:27][C:26]([O:30]CC4C=CC(OC)=CC=4)=[CH:25][C:24]=3[Cl:40])[NH:20]2)=[CH:16][CH:15]=1)=[O:13].Cl>C(Cl)Cl.CO.O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([C:23]3[C:24]([Cl:40])=[CH:25][C:26]([OH:30])=[CH:27][C:28]=3[Cl:29])[NH:20]2)=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1ccc(COc2cc(Cl)c(-c3cc4ccc(C(=O)Nc5ccc6ccccc6n5)cc4[nH]3)c(Cl)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2cc(-c3c(Cl)cc(O)cc3Cl)[nH]c2c1
Reaction time: 2.5 h

Procedure:
To a suspension of 2-[2,6-dichloro-4-(4-methoxybenzyloxy)-phenyl]-1H-indole-6-carboxylic acid quinolin-2-ylamide (200 mg, 0.352 mmol) in DCM (7.5 mL) and MeOH (2.5 mL) was added 4 M HCl in dioxane (7.5 mL) and the mixture was stirred for 2.5 hr. The reaction was concentrated under reduced pressured and the concentrate partitioned between EtOAc (150 mL) and sat NaHCO3 (30 mL). The organic phase was dried over Na2SO4 and the solvent evaporated. The residue was triturated with DCM to afford the title compound as an orange solid. MS (m/z) 448.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.72 (d, J=1.14 Hz, 1H), 11.04 (s, 1H), 10.68 (s, 1H), 8.36-8.43 (m, 2H), 8.18 (s, 1H), 7.96 (d, J=8.08 Hz, 1H), 7.89 (d, J=8.34 Hz, 1H), 7.79 (dd, J=8.34, 1.26 Hz, 1H), 7.74 (dd, J=15.35, 1.20 Hz, 1H), 7.66 (d, J=8.34 Hz, 1H), 7.52 (t, J=7.52 Hz, 1H), 7.02 (s, 2H), 6.53 (d, J=1.77 Hz, 1H).